Thalidomide Combinations Improve Response Rates; Results from the MRC IX Study.

Improving response rates represents an important way to improve PFS and OS in myeloma. In the MRC Myeloma VII study, now with a median follow up of 8 years, we showed the importance of achieving CR. The addition of thalidomide represents a way of increasing response rates. In the MRC Myeloma IX study, which has recruited 1800 patients, in two randomisations embracing younger and older patients, we have compared CTD with MP and CTD + HDM + ASCT with CVAD + HDM + ASCT. In addition to giving insight as to the impact of thalidomide on ORR and CR in both settings, we can assess the effects of HDM + ASCT following CTD induction. We have used a number of techniques to assess response in this study including protein electrophoresis, immunofixation and serum free light chain estimation combined with bone marrow aspiration and trephine assessment. This approach has been supplemented by sensitive multiparameter flow cytometry MRD analysis able to quantitate low levels of residual myeloma plasma cells. In a preliminary analysis, a thalidomide containing combination is associated with improved response rates. Post induction rates are CTD: ORR 95.7%, CR 20.3%; CVAD: ORR 83.4%, CR 11.7% and these differences are maintained at 100 days post HDM, CTD + HDM: ORR 98.7%, CR 58.2%; CVAD + HDM: ORR 95.7, CR 41%, showing that the ORR rate is higher and that the percentage of CR is doubled before HDM and 20% more following the HDM. The depth of CR is also greater in the cases receiving thalidomide. We are updating these results as well as the results from the MP vs CTD comparison and will present these data. There are some discrepancies between each of the disease monitoring approaches and optimally all should be used. At d+100 it is possible to have true CR measured by flow MRD assessment but still have detectable paraprotein. The opposite also occurs: apparent CR by paraprotein estimation with MRD positivity by flow. This has important implications for the definition of remission as well as for the assessment of new treatments and their use. Our findings suggest that thalidomide combinations significantly improve ORR, taking more patients to response levels which render them eligible for HDM + ASCT. CR rates are increased and there is a qualitative difference in the depth of CR obtained. The additive value of HDM + ASCT, even when thalidomide is used initially, is suggested by the further increase in the number of responses above that achieved by CTD alone. We await the follow up of patients entered into this large study to assess whether these increased and enhanced responses translate into improved PFS and OS.